Aicardi-Goutières Syndrome: Insights from a Middle Eastern Case Series

Aicardi-Goutières syndrome (AGS) is a rare, genetically-determined spectrum of neurodegenerative disorders that remains poorly understood. Owing to the paucity of data from the Middle Eastern population, we aimed to delineate the clinical, radiologic, and genetic features of AGS in an under-represented Middle Eastern cohort.

A retrospective case series review was performed of all genetically-confirmed AGS cases managed at a tertiary pediatric hospital in Qatar between November 2016 and December 2024. Demographic, clinical, radiologic, and genetic data were extracted; WM disease severity and imaging course were graded, and associations with genotype were explored.

Fifteen individuals (73.3% male; 80% consanguinity) were identified. Symptom onset occurred in the infantile age in 86.7%, with developmental delay or regression (100%), intellectual impairment (76.9%), and impaired motor function (69.2%) predominating. Two siblings with a SAMHD1-homozygous variant were neurologically normal but had chronic arthritis. Genetic variants were identified in RNASEH2B (26.7%), RNASEH2A, and TREX1 (each 20%), followed by ADAR1 and SAMHD1 (each 13.3%), and RNASEH2C (6.7%); 80% of variants were homozygous. Radiologic assessment was suggestive of the disease in 40% of the cases. Initial neuroimaging revealed focal WM disease in 76.9%, calcifications in 53.8%, hypomyelination in 38.5%, and basal ganglia involvement in 30.8%. WM disease was absent (13.3%), mild (40.0%), moderate (40%), or severe (6.7%); follow-up imaging showed stable (10%), regressive (30%), progressive (40%), or progressive-then-regressive (20%) course of imaging findings, independent of the genotype and clinical course. Genotype correlated significantly with WM disease severity at presentation (P < .05), but not with longitudinal imaging trajectory. Intrafamilial radiologic discordance was observed in one-half of the family clusters.

This AGS series from a Middle Eastern population broadens the phenotypic spectrum, highlighting high homozygosity and RNASEH2 predominance in a highly consanguineous population, a significant genotype-WM disease severity link, and radiologic variability independent of genotype or clinical course. Awareness of these patterns may inform population-based testing and management strategies.